Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia in Adults

The majority of adults with acute lymphoblastic leukemia will achieve a first complete remission (CR). However relapse is the most common cause of treatment failure. Outcomes after relapse remain poor, with long-term survival in the order of 10 %. Treatment decisions made at the time of first complete remission are thus critical to ensuring long-term survival. Allogeneic hematopoietic cell transplant (HCT) is effective at preventing relapse in many transplant recipients but is also associated with significant treatment related morbidity and mortality. Alternatively, ongoing systemic chemotherapy offers lower toxicity at the expense of increased relapse rates. Over the past decades, both the safety of transplant and the efficacy of non-transplant chemotherapy have improved. Emerging data show substantially improved outcomes for young adults treated with pediatric-inspired chemotherapy regimens that question the role of HCT in the upfront setting. In this review, we review the data supporting the role of allogeneic transplantation in adult acute lymphoblastic leukemia (ALL), and we propose a therapeutic algorithm for upfront therapy of adults with ALL.     

Philadelphia-Positive Acute Lymphoblastic Leukemia: Current Treatment Options

The Philadelphia chromosome (Ph), t(9;22), is seen in about 20?% to 30?% of adults diagnosed with acute lymphoblastic leukemia (ALL). It has been associated with poorer prognosis compared with Ph-negative ALL. Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL oncogenic protein from this translocation have been incorporated into treatment regimens used to treat patients with Ph-positive ALL. Imatinib has been the most widely used TKI with several published trials showing it produced better outcomes when combined with chemotherapy. Dasatinib, a more potent inhibitor than imatinib, has also been evaluated with promising results. However, relapses still occur at a high rate, and allogeneic stem cell transplant is considered, so far, a better curative option in first remission. Additional strategies have also included incorporation of TKIs in the post-transplant setting and the use of newer third generation TKIs. This review provides an update on emerging therapies for adults with Ph-positive ALL.     

成人急性淋巴细胞白血病治疗进展

【指示性摘要】尽管应用各种不同的诱导缓解方案,80％-95％的成人急性淋巴细胞白血病（ALL）可获得形态学上的完全缓解,但大部分病人很快复发。能否获得免疫学或分子水平的微小残留病（MRD）状态及达到MRD的速度极为重要。缓解后治疗是病人长期生存的关键。接受异基因移植的病人复发率明显降低。但在年龄35—40岁以上的移植患者中,较高的移植相关死亡率抵消了异基因移植的生存优势。相配无关供体移植的应用日益广泛,可用于所有高危病人。降低强度的移植可能增加老年患者的生存率。伊马替尼甲磺酸的应用彻底改变了ph阳性ALL的治疗方法,特别是该型老年患者。诊断时有CNS累及的患者,只要给予及时治疗,对预后无明显不利影响。     

Clinical manifestations and treatment of newly diagnosed acute lymphoblastic leukemia in adults

Adult acute lymphoblastic leukemia (ALL) is a heterogeneous disease with distinct biologic and prognostic subgroups. The treatment of adults with ALL has evolved largely from the therapy developed for childhood ALL and, despite differences across regimens, can be broadly classified as including induction, consolidation, maintenance, and central nervous system prophylaxis. Although there has been marked improvement in the outcomes for pediatric patients with ALL, the same success has not yet been realized for adult patients. Some of this difference can be attributed to a greater incidence of unfavorable cytogenetic subtypes in adults than in children. In addition, the ability to tolerate intensive regimens likely plays a role. This article reviews the classification, prognostic features, current treatment programs, and new advances as applied to adult patients with newly diagnosed ALL.     

Clinical manifestations and treatment of newly diagnosed acute lymphoblastic leukemia in adults

Adult acute lymphoblastic leukemia (ALL) is a heterogeneous disease with distinct biologic and prognostic subgroups. The treatment of adults with ALL has evolved largely from the therapy developed for childhood ALL and, despite differences across regimens, can be broadly classified as including induction, consolidation, maintenance, and central nervous system prophylaxis. Although there has been marked improvement in the outcomes for pediatric patients with ALL, the same success has not yet been realized for adult patients. Some of this difference can be attributed to a greater incidence of unfavorable cytogenetic subtypes in adults than in children. In addition, the ability to tolerate intensive regimens likely plays a role. This article reviews the classification, prognostic features, current treatment programs, and new advances as applied to adult patients with newly diagnosed ALL.     

Haemopoietic stem cell transplantation for acute lymphoblastic leukaemia

The majority of children and some adults with acute lymphocytic leukaemia (ALL) can be cured with current intensive chemotherapy regimens. For those patients who relapse or who do not achieve remission, allogeneic haemopoietic stem cell transplantation (HSCT) offers the best chance for long-term disease control. Different sources of haemopoietic stem cells including marrow, peripheral blood, and cord blood are now available and the introduction of subablative regimens has increased the number of patients who are transplant candidates. Relapse remains the major cause of transplant failure and immunotherapy strategies post-transplant to augment the graft versus leukaemia effect are being explored.     

Novel therapies for relapsed acute lymphoblastic leukemia

The outcome of salvage therapy for relapsed acute lymphoblastic leukemia (ALL) remains poor. Salvage therapy mimics regimens with activity in newly diagnosed ALL. Novel strategies under investigation as monotherapy or in combination with chemotherapy improve the treatment of relapsed disease. For some ALL subsets, specific therapies are indicated. The addition of targeted therapy in Philadelphia chromo some-positive ALL has improved responses in relapsed patients without resistance to available tyrosine kinase inhibitors. Nelarabine demonstrates activity as monotherapy in T-cell ALL and is approved by the US Food and Drug Administration. Clofarabine, a second-generation purine analogue approved in pediatric leukemia, has shown activity in adult acute leukemias including ALL and acute myeloid leukemia. The role of pegaspargase in adult ALL requires further investigation. The benefit of matched related-donor allogeneic stem cell transplantation is significant for standard-risk ALL but not for high-risk ALL. Development of new drugs and agents tailored to subset-specific cytogenetic-molecular characteristics remains vital to success in treating adult ALL.     

Meningeosis leukaemica in adult acute lymphoblastic leukaemia

This review addresses diagnosis of CNS involvement, incidence and treatment of CNS disease at time of diagnosis, prophylaxis and treatment of CNS relapse and risk factors for meningeal recurrence in adult acute lymphoblastic leukaemia (ALL).At the time of diagnosis meningeosis leukaemica is present in about 6% (1–10%) of the adult ALL patients with a higher incidence in ALL subgroups T-ALL (8%) and B-ALL (13%). With the invention of early additional CNS directed therapy it no longer represents an unfavourable prognostic factor.In the absence of prophylaxis meningeal relapses occur in approximately one third of adults with ALL. A literature review including more than 4000 adult ALL patients showed for the different prophylactic treatment approaches the following CNS relapse rates: intrathecal therapy alone 13% (8–19%), intrathecal therapy and CNS irradiation 15% (6–22%), high dose chemotherapy 14% (10–16%), high dose chemotherapy and intrathecal therapy 8% (2–16%) and high dose chemotherapy, intrathecal therapy together with CNS irradiation 5% (1–12%). It became obvious that the early onset of intrathecal therapy and CNS irradiation and the continuation of intrathecal administrations throughout maintenance are essential. The most favourable results where achieved with high dose chemotherapy combined with intrathecal therapy and/or CNS irradiation. The majority of treatment regimens in adult ALL already include high dose chemotherapy in order to reduce the risk of bone marrow relapse.The outcome of patients with CNS relapse is still poor. Although a remission can be induced in the majority of patients (> 60%) it is usually followed by a bone marrow relapse and the survival is poor (< 5–10%). Bone marrow transplantation might be in adults at present the only curative approach.     

Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia with imatinib in combination with chemotherapy

The presence of the Philadelphia chromosome (Ph) is associated with a very poor prognosis in acute lymphoblastic leukemia (ALL). Although hematologic complete remission (CR) is achieved in 50% to 80% of adult patients by intensive chemotherapy in multicenter studies, long-term outcome is dismal, with overall survival of approximately 10%. Currently, allogeneic hematopoietic stem cell transplantation (allo-SCT) is thought to be the only curative therapeutic modality for this leukemia in adults, but the long-term survival rates are about 40% or less, far from satisfactory. Imatinib mesylate, a recently introduced specific tyrosine kinase inhibitor of BCR-ABL, in combination with chemotherapy, resulted in more than 90% hematologic CR in adult Ph-positive ALL, including molecular CR in more than 50% of patients. The higher CR rate and less frequent relapse gave more patients a chance to receive SCT. Patients who did not qualify for allo-SCT because of the lack of a suitable donor, advanced age, or underlying medical conditions apparently showed better survival than historical control patients treated with chemotherapy alone. Although longer follow-up is required to determine the effect on survival, imatinib in combination with chemotherapy clearly has a major potential to improve the treatment of Ph-positive ALL and may cure a substantial proportion of patients without SCT.     

Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia with imatinib in combination with chemotherapy

The presence of the Philadelphia chromosome (Ph) is associated with a very poor prognosis in acute lymphoblastic leukemia (ALL). Although hematologic complete remission (CR) is achieved in 50% to 80% of adult patients by intensive chemotherapy in multicenter studies, long-term outcome is dismal, with overall survival of approximately 10%. Currently, allogeneic hematopoietic stem cell transplantation (allo-SCT) is thought to be the only curative therapeutic modality for this leukemia in adults, but the long-term survival rates are about 40% or less, far from satisfactory. Imatinib mesylate, a recently introduced specific tyrosine kinase inhibitor of BCR-ABL, in combination with chemotherapy, resulted in more than 90% hematologic CR in adult Ph-positive ALL, including molecular CR in more than 50% of patients. The higher CR rate and less frequent relapse gave more patients a chance to receive SCT. Patients who did not qualify for allo-SCT because of the lack of a suitable donor, advanced age, or underlying medical conditions apparently showed better survival than historical control patients treated with chemotherapy alone. Although longer follow-up is required to determine the effect on survival, imatinib in combination with chemotherapy clearly has a major potential to improve the treatment of Ph-positive ALL and may cure a substantial proportion of patients without SCT.     

Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia; Current Evidence,and Improving Outcomes Going Forward

Purpose of Review

Outcomes for older adults with acute lymphoblastic leukemia (ALL) remain poor, and allogeneic hematopoietic stem cell transplant (HSCT) remains a potentially curative modality. However, benefits are offset by high rates of non-relapse mortality (NRM) in patients undergoing myeloablative conditioning (MAC) regimens. Reduced intensity conditioning (RIC) regimens can extend this therapy to adults who are unfit for MAC, although at the cost of higher relapse rates. In this review, we discuss evidence to support the usage of RIC regimens, controversies, and potential strategies to improve transplant outcomes going forward.

Recent Findings

Several novel therapies have recently been approved for the treatment of relapsed ALL and may play an important role in bridging adults with residual disease to RIC transplant. Assessing response to initial therapy via minimal residual disease (MRD) monitoring may determine which patients will derive the most benefit from allogeneic HSCT.

Summary

Reduced intensity allogeneic HSCT remains a potentially curative therapy that can be offered to older adults however challenges remain. Going forward, MRD testing and novel therapies may help better select which patients should proceed to transplant and assist in getting those patients to transplant with optimally controlled disease.

     

Early allogeneic transplantation for refractory or relapsed acute leukaemia following remission induction with FLAG.

The prognosis for patients with secondary AML, primary resistant AML or ALL and early (<12 months) relapse of acute leukaemia remains extremely poor with conventional chemotherapy. As part of a strategy to improve the outcome for these patients we have treated 22 consecutive patients (18 AML, four ALL, median age 35 years) with either primary resistant disease (n=3), early relapsed leukaemia (n= 12) or secondary AML (n= 7, four RAEBt, two antecedant ALL and one antecedant Hodgkin's disease) with 'FLAG' induction chemotherapy with the aim of proceeding to early allogeneic transplantation either from sibling or unrelated donors. Eighteen patients achieved CR after one course of FLAG, including five patients who had documented p-glycoprotein-induced multidrug resistance and 10 patients with adverse cytogenetic abnormalities. Eight patients were consolidated with a second course of FLAG prior to transplantation and so far 16 patients have undergone allogeneic transplantation, 10 from unrelated donors and six from sibling donors (one mismatched). By the time of transplant three patients had progressed and were in early relapse and all have relapsed post BMT. Of the remaining 13 patients transplanted in remission, nine remain in CCR at a range of 4-26 months, three have died of transplant-related complications (18%) and one patient has relapsed. We conclude that the use of FLAG induction therapy followed by early allogeneic transplantation from either a sibling or unrelated donor can be an effective strategy for the treatment of this difficult group of young patients with poor risk acute leukaemia and appears to be associated with a low procedure-related risk.     

Organ transplant-related lymphoma

Opinion statement] Post-transplant lymphoproliferative disorder is a curable disease in which a wide range of treatment strategies has met with a degree of success. Both the disease and the organ transplant setting in which it occurs are highly variable. A sequential approach to treatment is preferred, starting with reduction in immunosuppressives. Rituximab or interferon alfa can be tried next, in the hope of avoiding chemotherapy. Rituximab has significant activity and has shown no additional toxicities in transplant recipients. It may be appropriate to add rituximab to the initial treatment in critically ill patients. Cytotoxic chemotherapy is effective but significantly more toxic in this patient population. Effective therapy should be instituted before progressive disease results in declining performance status and multi-organ dysfunction. The goal of treatment is complete and durable remission. Adoptive T-cell therapy is an effective and promising alternative for allogeneic bone marrow transplant recipients.     

Olverembatinib Treatment in Pediatric Patients With Relapsed Philadelphia-Chromosome-Positive Acute Lymphoblastic Leukemia

Treatment outcomes for children with Philadelphia chromosome-positive (Ph⁺) acute lymphoblastic leukemia (ALL) remained poor despite the use of intensive chemotherapy, imatinib or dasatinib, and consolidative allogeneic hematopoietic cell transplantation. Oleverembatinib, a third-generation ABL inhibitor, was found to be highly effective and safe in adults with chronic myeloid leukemia and in some adults with relapsed or refractory Ph⁺ ALL. We reviewed the efficacy and safety profile of olverembatinib treatment in 6 children with relapsed Ph⁺ ALL and 1 with T-ALL and ABL class fusion, all of whom had previously received dasatinib or intolerance to dasatinib. The median duration of olverembatinib treatment was 70 days (range: 4-340) and the median cumulative dose was 600 mg (range: 80-3810). Complete remission with negative minimal residual level (<0.01%) was achieved in 4 of the 5 evaluable patients, 2 of whom were treated with olvermbatinib as a single agent. Safety profile in 6 evaluable patients was excellent with grade 2 extremity pain occurred in 2 patients and grade 2 myopathy of lower extremity and grade 3 fever in 1 patient each. Olverembatinib appeared to be safe and effective in children with relapsed Ph⁺ ALL.     

Intensive retreatment of adults and children with acute lymphoblastic leukemia.

Twenty-three patients (16 adults) failing their first or subsequent (n = 8) intensive treatment for de novo acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia lymphoid blast phase (n = 2) were managed with protocol POG 8201, originally introduced in relapsed ALL of childhood. In this programme, a four-drug induction phase is followed by early consolidation with teniposide-cytarabine, intrathecal chemotherapy, continuation weekly chemotherapy alternating teniposide-cytarabine with vincristine-cyclophosphamide, and periodic reinduction courses. Fourteen adults and five children with ALL achieved a complete response (CR) (86 per cent). The highest response rate (100 per cent) was obtained in 12 patients treated at first relapse after an initial CR of greater than 18 months (p = 0.07). Median duration of CR was 8 months in adults and 11 months in children. A longer than previous one CR (inversion) was obtained in four cases. Four ALL patients were successfully transplanted from a matched sibling after 3-11 months from achievement of CR. Median overall survival in adults with ALL was 11 months, significantly longer than for 40 comparable cases treated intensively but without rotational continuation therapy in previous years (p less than 0.001). This regimen is applicable to adults with relapsed ALL, where prolongation of survival may allow time for effective salvage with bone marrow transplantation.     

Treatment of Young Adults with Acute Lymphoblastic Leukemia

Young adults with acute lymphoblastic leukemia are a distinctive category of patients, with substantial difference in disease biology and response to therapy; hence, they pose unique challenges and issues beyond those faced by children and older adults. Despite inferior survival compared to children, there is growing evidence to suggest that young adults have improved outcomes when treated with pediatric-based approaches. With better supportive care and toxicity management and multidisciplinary team and approach, we have made great improvement in outcomes of young adults with ALL. However, despite significant progress, patients with persistence of minimal residual disease have a poor prognosis. This review discusses current controversies in the management of young adults with ALL, outcomes following pediatric and adult protocols, and the role of allogeneic stem cell transplantation. We also explore recent advances in disease monitoring and highlight our approach to incorporation of novel therapies in the management of young adults with ALL.     

Dose-intensive therapy for adult acute lymphoblastic leukemia

Major challenges remain to be overcome to increase the cure rate for acute lymphoblastic leukemia (ALL), especially for middle-aged and older adults. Despite high rates of complete remission (CR), many patients relapse after chemotherapy alone. Dose-intensive therapy and stem-cell transplantation (SCT) have been able to rescue some of these patients. However, many patients presently are being cured using intensive consolidation chemotherapy during first remission (CRI) and at a lower cost and toxicity than with SCT. The use of SCT in CRI should be governed by an assessment of known risk factors. Among younger adults in the prime transplant age group (< 50 years), there is no advantage to allogeneic (allo)-SCT across the board, but it is recommended for those with Philadelphia chromosome-positive (Ph+) ALL or pro-B ALL with t(4;11) and possibly for those with B-lineage ALL and initial WBC counts > 100,000/microL. There is as yet no evidence that allo-SCT can improve the already high cure rate achieved with chemotherapy alone in favorable subsets such as T-cell ALL. There appears to be no advantage to autologous (auto)-SCT over chemotherapy for consolidation of either high-risk or standard-risk patients in CRI. The argument that early use of auto-SCT shortens the duration of treatment and thereby improves the quality of life is not persuasive, as there is little morbidity from maintenance chemotherapy. Patients who receive a modern, intensive multiagent chemotherapy program for CRI but later relapse are unlikely to be cured with additional chemotherapy alone. High-grade multidrug resistance develops rapidly. These patients should undergo allo-SCT if possible. Unfortunately, allo-SCT is available to only a minority of such patients because of the lack of a donor or insurance coverage, or the presence of comorbid conditions or older age. The use of alternative donors (either matched, unrelated donors or partially human leukocyte antigen [HLA] matched family members) is appropriate in this circumstance. Auto-SCT with or without previously used purging methods is ineffective for patients with advanced ALL.     

Recent progress in the treatment of acute leukemia

Acute leukemia is classified broadly as either acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL). The main treatments remain remission induction therapy and postremission chemotherapy. The advances in chemotherapy for pediatric patients with ALL have been dramatic, with some 95% achieving complete remission, and long-term survival is 60-80%. Among adults, high long-term survival rates due to improvements in chemotherapy for B-cell type ALL and core binding factor leukemias have been reported. For adult leukemias overall, however, long-term survival rates have stalled at 15-40% despite the high remission rate attained. In most cases this is due to a recurrence. Among the prognostic factors reported for acute leukemia, chromosome type may be cited as the currently most reliable. Acute leukemia patients are classified based on chromosome type, and the postremission therapeutic strategy is considered in terms of an appropriate combination of chemotherapy and hematopoietic stem cell transplant. This accounts for an important part of the treatment given today. Target-based therapies such as all-trans-retinoic acid (ATRA) for AML have brought dramatic improvements in treatment results. The effect of imanitib against Philadelphia chromosome positive ALL, for which the prognosis is poor, is also attracting attention. Moreover, promising new treatment strategies that have been developed, including cord blood transplant, mini-transplant, antibody therapy, and immunotherapy, Clinical studies of PCR and other means to reveal small residual lesions and estimate prognosis are also making progress. In the future it will be possible to identify prognostic factors in genetic tests such as DNA microarrays and single nucleotide polymorphisms, so that the optimum treatment can be selected for individual patients.     

Improved survival of children with isolated CNS relapse of acute lymphoblastic leukemia: a pediatric oncology group study .

PURPOSE: Isolated meningeal relapse in children with acute lymphoblastic leukemia (ALL) usually has been followed by bone marrow relapse and limited survival. The purpose of this study was to prevent marrow relapse by administering intensive therapy before delayed craniospinal radiation. PATIENTS AND METHODS: Eighty-three patients with ALL in first bone marrow remission with an isolated CNS relapse were treated with systemic chemotherapy known to enter into the CSF and intrathecal chemotherapy for 6 months. Craniospinal irradiation (24 Gy cranial/15 Gy spinal) was then administered, followed by 1.5 years of maintenance chemotherapy. RESULTS: All 83 patients achieved a second remission. The 4-year event-free survival (EFS) rate was 71.1% +/- 5.3%. There was a fourfold increased risk of relapse for children whose initial remission was less than 18 months. The 4-year EFS rate for patients with a first complete remission >/= 18 months was 83.3% +/- 5.3%, and for those with a first complete remission less than 18 months, it was 46.2% +/- 10.2% (P =.0002.) There was a low incidence of neurologic toxicity and an unexpectedly high rate of allergic reactions to L-asparaginase. Five patients developed secondary malignancies: two with acute nonlymphoblastic leukemia during therapy, one with myelodysplasia after therapy, and two with brain tumors 1.5 to 2 years after cessation of therapy. CONCLUSION: For children with ALL and an isolated CNS relapse, treatment that delays definitive craniospinal irradiation by 6 months to allow for more intensive systemic and intrathecal chemotherapy results in better EFS than has been previously reported. Using this approach, the long-term prognosis for children with first complete remission >/= 18 months is comparable to that at the time of original diagnosis of ALL.     

SOHO State of the Art Updates & Next Questions: Intensive and Non–Intensive Approaches for Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) was historically considered to be a very poor-risk subtype of ALL. However, with the introduction of highly potent BCR-ABL tyrosine kinase inhibitors (TKIs), Ph+ ALL can now be considered relatively favorable-risk acute leukemia. Considering the high rates of measurable residual disease negativity and excellent long-term survival that has been achieved with regimens incorporating later-generation TKIs and particularly with ponatinib, lower-intensity and even chemotherapy-free regimens are now being evaluated for patients of all ages with Ph+ ALL. The very encouraging early results observed with blinatumomab-based, chemotherapy-free regimens challenge previous notions that all patients with Ph+ ALL should undergo allogeneic stem cell transplantation in first remission, as these regimens are capable of achieving deep and durable remissions without need for transplant in the vast majority of patients, particularly when combined with ponatinib. In this review, we discuss the evolving approach to the treatment of adults with newly diagnosed Ph+ ALL and the major principles that should guide therapy in this disease. We also review the rationale and data supporting the use of novel, chemotherapy-free regimens in Ph+ ALL, and how these approaches may soon become new standards of care.