Alemtuzumab for haematological malignancies

T-cell large granular lymphocytic (T-LGL) leukemia is an indolent lymphoproliferative disorder characterized by clonal expansion of large granular lymphocytes and generally favorable prognosis [30]. While standard treatment includes immunosuppressive therapies such as methotrexate, cyclosporine, and cyclophosphamide, a subset of patients remains refractory, necessitating alternative strategies [30].

Alemtuzumab has been sparsely reported in T-LGL treatment, though case studies suggest promising efficacy. Olteanu et al. described a 63-year-old female with multi-refractory T-LGL, who achieved long-term hematologic remission following alemtuzumab therapy, with sustained responses over seven years [31]. Similarly, Monjanel et al. reported a case of refractory T-LGL leukemia in which alemtuzumab induced deep molecular remission, confirmed by PCR-based detection of clonal T-cell disappearance [32]. Further supporting these observations, a Phase II trial conducted in the United States further validated these observations, reporting a 56% hematologic response rate among 25 patients with refractory T-LGL leukemia. Notably, in patients without prior myelodysplastic syndrome (MDS) or allogeneic stem cell transplantation, the response rate increased to 74%. The majority of responders exhibited hematologic improvement within 2–3 weeks, and responses were sustained in over 50% of patients. Alemtuzumab was generally well tolerated, with transient infusion reactions and Epstein-Barr virus (EBV) / cytomegalovirus (CMV) reactivation being the most commonly observed adverse effects, but without significant opportunistic infections [33]. Although alemtuzumab remains an investigational treatment for T-LGL, its promising efficacy in refractory cases suggests its potential inclusion in treatment algorithms for patients unresponsive to conventional immunosuppressive therapy. Future research should focus on optimizing dosing regimens and assessing long-term safety to balance therapeutic benefits with potential risks.

Alemtuzumab has shown significant potential in treating lymphoma. A U.S. phase II study demonstrated an ORR of 52% in adults with T-cell leukemia/lymphoma (ATL) [34]. Furthermore, a randomized controlled phase III trial in Germany found that the combination of alemtuzumab with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) resulted in a higher ORR in patients with peripheral T-cell lymphoma (PTCL) compared to CHOP alone (72% vs. 66%) [35]. However, despite the improved ORR, no increase in OS was observed, primarily due to treatment-related toxicities.

In an additional phase II clinical trial conducted in Asia, the combination of alemtuzumab with CHOP yielded an ORR of 80% in untreated PTCL patients [36]. For patients with relapsed/refractory PTCL, the combination of alemtuzumab with DHAP (dexamethasone, cytarabine, and cisplatin) achieved an ORR of 50%, while unspecified PTCL patients reached an ORR of 69.2% [37]. Moreover, a case report from China described significant improvement in a patient with cutaneous T-cell lymphoma after treatment with topical nitrogen mustard and alemtuzumab [38]. These findings underscore alemtuzumab’s therapeutic potential in lymphoma, particularly among Asian populations. Nonetheless, further studies are required to fully understand its impact on long-term survival and to mitigate treatment-related toxicities.

Alemtuzumab possesses immunosuppressive properties that lead to prolonged lymphocyte depletion with minimal effects on other immune cells, such as monocytes, NK cells, dendritic cells, and neutrophils. This targeted immunosuppression has demonstrated efficacy in treating AA [39]. In one study, patients with anti-thymocyte globulin (ATG)-refractory severe AA (SAA) responded favorably to alemtuzumab, exhibiting reduced toxicity. A clinical trial conducted in Mexico reported a response rate of 57% among 14 AA patients [40]. Similarly, a study in South Korea found a 37% response rate in a cohort of 17 AA patients [41]. A subsequent phase II clinical study in the United States evaluated alemtuzumab as monotherapy for primary, relapsed, and refractory SAA. Although the remission rate for alemtuzumab was lower in the primary treatment setting (19%) compared to horse ATG (hATG) and rabbit ATG (rATG), alemtuzumab demonstrated efficacy in refractory or relapsed cases, with a 6-month hematologic remission rate of 37% and a 3-year survival rate of 83%, compared to 33% and 60% for rATG, respectively [42].

Alemtuzumab is frequently used in combination with chemotherapy as a preconditioning agent for HSCT in patients with acute leukemia or myelodysplastic syndromes (MDS). This regimen not only aims to eradicate tumor cells but also to mitigate the risk of GVHD. An observational study in the United Kingdom reported that MDS patients receiving reduced-intensity conditioning with fludarabine, busulfan, and alemtuzumab had a one-year survival rate of 73% for related donors and 71% for unrelated donors. The cumulative incidence of grade III-IV acute GVHD was 0% and 9%, respectively [43]. Furthermore, reduced-intensity conditioning regimens incorporating alemtuzumab have been associated with significant reductions in both acute and chronic GVHD [44]. A U.S. phase II trial involving patients with acute myeloid leukemia (AML) and MDS, who had poor performance status or comorbidities, employed a reduced-intensity preconditioning regimen of fludarabine, melphalan, and alemtuzumab. The study found one-year post-transplant survival and PFS rates of 48% and 38%, respectively. The cumulative incidence of extensive GVHD was 18%, underscoring the potential of alemtuzumab-containing regimens for AML and MDS patients [45]. Additionally, a retrospective study found that the FCA regimen (fludarabine, low-dose cyclophosphamide, and alemtuzumab) reduced the incidence of GVHD in older patients with severe aplastic anemia undergoing allogeneic HSCT, with outcomes comparable to younger patients [46].

Alemtuzumab not only prevents GVHD before transplantation but also reduces the incidence of chronic GVHD following transplantation, particularly in high-risk acute leukemia patients. A European retrospective cohort study demonstrated that low-dose alemtuzumab effectively prevented GVHD after prophylactic donor lymphocyte infusions (pDLIs) in high-risk patients [47]. In a randomized, single-center, open-label, phase II trial conducted in the United States, high-dose alemtuzumab combined with cyclosporine (AC) was compared to tacrolimus-methotrexate-sirolimus (TMS) for chronic GVHD prevention. The AC group exhibited a significantly lower incidence of severe chronic GVHD compared to the TMS group at both 1 and 5 years (0% vs. 10.3% and 4.5% vs. 28.5%, respectively; p = 0.0002) [48]. Alemtuzumab has also shown substantial therapeutic efficacy in the treatment of steroid-refractory acute GVHD (SR-aGVHD). A European retrospective cohort study reported that 17 out of 18 SR-aGVHD patients responded to alemtuzumab, with five achieving CR [49]. Similarly, an Australian phase II study found that three out of four SR-aGVHD patients achieved CR, with one patient achieving partial remission after 28 days of alemtuzumab treatment [50]. Among pediatric and young adult patients with SR-aGVHD, alemtuzumab demonstrated an ORR of 67%, with a CR rate of 40% and a partial remission (PR) rate of 27% [51]. These findings underscore alemtuzumab’s clinical utility in both preventing and managing post-transplant GVHD, particularly in high-risk patients.

Alemtuzumab is also employed as a preconditioning agent for CAR-T cell therapy. In two phase I clinical trials involving patients with CD19-positive B-ALL who had failed standard treatments, alemtuzumab was included in FC or FCA preconditioning regimens prior to UCART19 cell therapy [52]. High serum levels of alemtuzumab were associated with the expansion of UCART19 cells in vivo, whereas patients without alemtuzumab preconditioning exhibited no detectable UCART19 cell expansion or graft-versus-leukemia (GVL) effect. These results suggest that alemtuzumab creates an immunosuppressive environment conducive to CAR-T cell expansion. The overall ORR for UCART19 therapy was 67%, rising to 82% in patients receiving FCA preconditioning, with only one of 21 patients developing acute GVHD. A recent phase I clinical trial in China involving relapsed/refractory B-ALL patients used FCA preconditioning for dual CD19/CD22-targeted universal CAR-T cell therapy (CTA101), achieving an ORR of 83.3%. All patients achieved MRD-negative CR, and no cases of acute GVHD were reported. Another phase I study employed an FC or FCA preconditioning regimen followed by a single dose of UCART22. Preliminary results indicated that 60% of patients receiving the FCA regimen demonstrated antitumor activity at dose level 3 (DL3), with one patient maintaining MRD-negative CR for over six months post-treatment [6].

Infusion-related reactions (IARs) are typically characterized by symptoms such as chills, fever, nausea, vomiting, and rash, which manifest during or within 24 h following alemtuzumab administration. A clinical trial conducted in Korea observed that the majority of IARs were mild to moderate rashes that resolved spontaneously [37]. It is advised that if grade 3 or 4 IARs occur during treatment, administration of alemtuzumab should continue at a reduced dose until these toxicities subside to grade 1 or lower [34].

Preventive measures, including the use of gastric mucosal protectants and methylprednisolone, have proven effective in mitigating the incidence of IARs. Across two treatment courses, the incidence rates of IARs were 91.4% and 81.5%, respectively, with severe IARs reported in 15.5% of cases. Although most patients experience IARs, these prophylactic interventions appear to reduce both the frequency and severity of alemtuzumab-induced rashes [53]. Management strategies for IARs include temporarily interrupting or slowing the infusion, administering medications such as corticosteroids, and providing patient education and support [54].

The U.S. FDA prescribing information recommends that alemtuzumab be administered in healthcare facilities equipped to manage severe infusion reactions, with patients closely monitored for at least two hours post-infusion. These guidelines emphasize the necessity of proactive management to mitigate the impact of adverse events associated with alemtuzumab therapy.

Hematologic toxicities, including lymphocytopenia, leukopenia, and thrombocytopenia, are among the most commonly reported adverse events in association with alemtuzumab, as recorded in the U.S. FDA Adverse Event Reporting System (FAERS) [55]. These toxicities typically manifest within the first month of alemtuzumab monotherapy [22]. A Phase I clinical trial in Japan involving B-CLL treatment observed that anemia and neutropenia (in 6 out of 6 patients) and thrombocytopenia (in 5 out of 6 patients) were the most frequently reported hematologic toxicities [19]. Additionally, Phase II clinical trials conducted in Asian populations showed elevated rates of grade 3/4 leukopenia or neutropenia (79.2% and 90.0%, respectively) when alemtuzumab was combined with DHAP or CHOP for treating relapsed/refractory peripheral T-cell lymphoma (PTCL) [29, 37]. A Phase III clinical trial in France comparing the FCR and FCA regimens for CLL treatment reported a higher incidence of grade 3 neutropenia in the FCA regimen group compared to the FCR group (38.7% vs. 29.6%, P = 0.023). However, no significant difference was observed in the incidence of grade 4 neutropenia between the two groups (25.3% vs. 19.4%, P = 0.130) [56].

To manage hematologic toxicities, the FDA recommends close monitoring of hematologic parameters in patients undergoing alemtuzumab therapy to enable timely intervention and prevent complications.

The immunosuppressive effects of alemtuzumab significantly elevate the risk of infection-related complications. Documented infections in prior clinical trials include mucormycosis, Pseudomonas aeruginosa, Escherichia coli, and reactivation of cytomegalovirus, with similar patterns observed in Asian cohorts [36, 57‐60]. A study conducted in Hong Kong reported that alemtuzumab therapy in patients with hematologic malignancies could lead to tuberculosis reactivation, with reactivation rates of 31% at one year and 45% at two years post-treatment [61]. Another domestic study documented a case of Pneumocystis jirovecii pneumonia (PCP) following alemtuzumab therapy, where the patient achieved full recovery after receiving trimethoprim-sulfamethoxazole (SMZ) therapy [62]. Although high-risk CLL patients treated with alemtuzumab exhibited a 2.5-fold increase in opportunistic infections compared to those receiving conventional FC chemotherapy, there was no corresponding increase in treatment-related mortality [24].

These findings underscore the importance of proactive prevention and management of infection-related complications. The FDA advises patients undergoing alemtuzumab therapy to immediately report any symptoms of infection, such as fever, and to take prophylactic medications for PCP and viral infections. In clinical practice, SMZ is routinely used for PCP prevention, fluconazole for fungal infections, and valacyclovir or ganciclovir for viral infections [22, 24, 56, 63].

Alemtuzumab-induced immune reconstitution may result in the development of autoimmune diseases, including thyroid disorders, immune thrombocytopenic purpura (ITP), and immune nephropathy [64]. Alemtuzumab is more commonly employed in the treatment of autoimmune conditions in multiple sclerosis, with these disorders typically emerging within the first three years of treatment [65‐66]. For example, a report from Japan documented a case of autoimmune hemolytic anemia following haploidentical hematopoietic stem cell transplantation with alemtuzumab in a patient with MDS [67]. A Canadian expert consensus highlighted that autoimmune diseases associated with alemtuzumab are generally predictable and identifiable, thereby facilitating effective management through early detection and intervention [68]. In line with these findings, the FDA recommends regular monitoring of blood counts, serum creatinine, and urine cell counts for up to 48 months following alemtuzumab therapy to mitigate the risk of severe autoimmune diseases.

Alemtuzumab has also been linked to other rare but serious adverse events, including hepatotoxicity, cardiotoxicity, stroke, carotid artery dissection, and secondary malignancies [29, 69, 70]. In response to reports of stroke and/or carotid artery dissection in 13 patients with relapsing-remitting multiple sclerosis treated with alemtuzumab, the FDA updated the “Warnings and Precautions” section of the prescribing information for alemtuzumab in 2018. Although these rare events have been primarily observed in patients with multiple sclerosis, they warrant careful consideration in the context of hematologic malignancies.

Alemtuzumab has emerged as a valuable therapeutic agent, demonstrating significant clinical efficacy in the treatment of B-CLL. Beyond B-CLL, alemtuzumab has shown potential therapeutic benefits in other hematologic malignancies, including lymphoma, acute leukemia, MDS, GVHD, and as part of CAR-T cell therapies. Although the majority of safety and efficacy data originate from international studies, further research in diverse demographic populations is necessary to enhance understanding and validation of its efficacy on a global scale.

While alemtuzumab’s broad application is promising, it also presents notable safety challenges, particularly concerning immunosuppression-induced infections, autoimmune diseases, and other rare but serious adverse events. Future clinical research should focus on optimizing combination therapy strategies to improve therapeutic efficacy while minimizing the risk of severe adverse events. Effective risk management and timely interventions will be essential to maximizing alemtuzumab’s therapeutic benefits and mitigating its associated risks.

In conclusion, alemtuzumab holds considerable promise for the treatment of hematologic malignancies. As clinical research advances, particularly in the optimization of combination therapies and the improvement of safety management, alemtuzumab is poised to become an integral component of hematologic cancer treatment. Ongoing accumulation of clinical evidence and real-world experience will enable a more comprehensive understanding of its therapeutic potential, providing patients with safer and more effective treatment options.