Philadelphia-chromosome-positive adult acute lymphocytic leukemia: Characteristics, treatment results, and prognosis in 41 patients

doi:10.1016/0002-9343(94)90049-3

The American Journal of Medicine

Volume 97, Issue 1, July 1994, Pages 60-65

https://doi.org/10.1016/0002-9343(94)90049-3 Get rights and content

Abstract

background: Philadelphia-Chromosome-positive (Ph-positive) acute lymphocytic leukemia (ALL) is associated with poor outcome in children as well as in adults. We report our experience in patients with Ph-positive ALL and review their clinico-laboratory characteristics, response to different therapies, and overall prognosis.

patients and methods: Since 1980, 41 newly diagnosed patients with Ph-positive ALL were referred to our service. In addition to confirmation of their diagnosis by morphologic studies of bone marrow aspiration and biopsy specimens, patients underwent cytogenetic, immunophenotypic, and molecular studies. Thirty-five patients received vincristine-Adriamycin-dexamethasone (VAD) or cyclophosphamide (CVAD) induction regimens, and 6 patients were treated with other combinations. Thirty-seven patients received salvage therapy that included VAD, high-dose cytosine arabinoside (ara-C)-containing regimens, methotrexate-asparaginase, and high-dose chemotherapy with autologous or allogeneic bone marrow transplantation (BMT).

results: The 41 patients were among 334 patients with ALL (12%) seen during that same period. Patients with Ph-positive ALL were older and had a significantly lower incidence of anemia and a higher incidence of peripheral leukocytosis, FAB L₂ (Fench-American-British) morphology, common acute lymphocytic leukemia antigens (CALLA), and CD34 marker positivity. With induction chemotherapy, 23 of 41 Ph-positive ALL patients (56%) achieved complete remission, and their median survival and remission duration were 11 months and 9 months, respectively. Thirteen of 31 Ph-positive ALL patients (42%) achieved complete response with high-dose ara-C regimens during salvage therapy.

conclusions: In our experience, patients with Ph-positive ALL are usually older, have FAB L₂ morphology, and are CALLA-positive and CD34-positive. These patients have a poor prognosis when treated with conventional approaches with lower overall complete response rate, shorter remission duration, and shorter survival. There appears to be a selective sensitivity to high-dose ara-C in these patients that suggests a possible role of this agent as part of early consolidation or induction regimens.

References (31)

R Walters et al.
The importance of cytogenetic studies in adult acute lymphocytic leukemia
Am J Med
(1990)
JA Fletcher et al.
Prognostic implications of cytogenetic studies in an intensively treated group of children with acute lymphoblastic leukemia
Blood
(1989)
W Crist et al.
Philadelphia chromosome positive childhood acute lymphoblastic leukemia: clinical and cytogenetic characteristics and treatment outcome
JR Priest et al.
Philadelphia chromosome positive childhood acute lymphoblastic leukemia
Blood
(1980)
AJ Barrett et al.
Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia
Blood
(1992)
SJ Forman et al.
Bone marrow transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia
Blood
(1987)
HM Kantarjian et al.
Phase I-II clinical and pharmacologic studies of high-dose cytosine arabinoside in refractory leukemia
Am J Med
(1986)
HM Kantarjian et al.
Significance of the p210 versus p190 molecular abnormalities in adults with Philadelphia chromosome-positive acute leukemia
Blood
(1991)
CD Bloomfield et al.
The Philadelphia chromosome in adults presenting with acute leukemia
LM Secker-Walker et al.
Philadelphia positive acute lymphoblastic leukemia in adults: age distribution, bcr breakpoint and prognostic significance
Leukemia
(1991)

N Heisterkamp et al.

Structural organization of the bcr gene and its role in the Ph' translocation

Nature

(1985)

Y Ben-Neriah et al.

The chronic myelogenous leukemia-specific p210 protein is the product of the bcr/abl hybrid gene

Science

(1986)

R Kurzrock et al.

The molecular genetics of Philadelphia chromosome-positive leukemias

NEJM

(1988)

E Fainstein et al.

A new fused transcript in Philadelphia chromosome positive acute lymphocytic leukemia

Nature

(1987)

LC Chan et al.

A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia

Nature

(1987)

Cited by (104)

Favorable outcome of unrelated cord blood transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia
2011, Biology of Blood and Marrow Transplantation
Citation Excerpt :
Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) accounts for 20%-30% of cases of adult ALL [1]. Ph+ALL is an aggressive disease with a poor prognosis, and it is not curable when treated by standard chemotherapy alone [2-5]. The results of recent clinical trials suggest that allogeneic hematopoietic stem cell transplantation (allo-HSCT) after imatinib-incorporating induction chemotherapy may be a promising option to overcome Ph+ALL [6-10].
Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph⁺ALL) is one of the highest-risk ALL groups. Whenever possible, patients with Ph⁺ALL should undergo allogeneic hematopoietic stem cell transplantation (HSCT) after induction of remission. Although unrelated cord blood transplantation (CBT) has become a common treatment in adult patients who lack a sibling donor, data on the efficacy of CBT for Ph⁺ALL are limited. We analyzed the clinical outcomes of 20 Ph⁺ALL patients who underwent CBT (n = 8) or unrelated bone marrow transplantation (BMT) (n = 12). The median age was 41 years (range, 17-55 years). All but one of the patients were treated with an imatinib-based regimen before HSCT, and 19 patients were in first complete remission (CR) and 1 patient was in second CR at the time of HSCT. Seventeen patients received a myeloablative conditioning regimen containing 12 Gy of total-body irradiation, and 3 received a reduced-intensity conditioning regimen. After a median of 26 months of follow-up, estimated 3-year overall and leukemia-free survival rates were 100% and 85%, respectively, after CBT, and 49% and 38%, respectively, after unrelated BMT. The CBT group had significantly better overall survival than the BMT group (P = .02). Although BCR-ABL transcript was detected in 4 of 8 CBT patients at transplantation, 7 patients remained in molecular CR. Our findings suggest that CBT may be a viable option as postinduction therapy for Ph⁺ALL in patients lacking a sibling donor.
Is AP24534 (Ponatinib) the next treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia?
2011, Bulletin du Cancer
Différents sous-types de leucémies aiguës lymphoblastiques (LAL) ont été individualisés, conduisant à l’utilisation de traitements adaptés au risque. Pour les LAL à chromosome Philadelphie (Ph⁺), le traitement optimal comprend actuellement l’association de chimiothérapie et d’un inhibiteur de la tyrosine kinase BCR-ABL, l’imatinib. Cependant, les résultats restent péjoratifs en l’absence de consolidation par une allogreffe de cellules souches hématopoïétiques. L’apparition de résistances liées à des mutations survenant dans le domaine kinase peut conduire à un échec thérapeutique malgré le recours aux inhibiteurs de seconde génération, le dasatinib ou le nilotinib. La résistance de la mutation BCR-ABL T315I à ces trois inhibiteurs de tyrosine kinases reste un challenge clinique majeur et le développement de nouveaux agents thérapeutiques semble indispensable. Les premières études sur l’AP24534 présentent cette nouvelle molécule comme un puissant inhibiteur de tyrosine kinases, actif sur la mutation T315I et les autres mutants de BCR-ABL. L’AP24534 pourrait être le prochain traitement de choix des hémopathies à chromosome Philadelphie, dont la LAL Ph⁺ connue pour son association fréquente à la mutation T315I.
Distinct clinicopathologic acute lymphoblastic leukemia (ALL) entities have been identified, resulting in the adoption of risk-oriented treatment approaches. In Philadelphia chromosome-positive (Ph⁺) ALL, the optimal treatment requires the addition of BCR-ABL tyrosine kinase inhibitors, as imatinib. However, the outcome remains poor in absence of allogeneic stem cell transplantation, and novel agents are desperately required. Resistance attributable to kinase domain mutations can lead to relapse despite the development of second-generation compounds, including dasatinib and nilotinib. Despite these therapeutic options, the cross-resistant BCR-ABL ^T315I mutation remains a major clinical challenge. The first evaluations of AP24534 present this drug as a potent multi-targeted kinase inhibitor active against T315I and all other BCR-ABL mutants. AP24534 could be the next treatment of choice in hematological malignancies with Philadelphia-positive chromosome, particularly Ph⁺ ALL known for its frequent occurrence of T315I mutation.
How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia
2010, Blood
The Philadelphia chromosome is present in approximately 20% to 30% of adults with acute lymphoblastic leukemia (ALL). The poor prognosis of this relatively uncommon acute leukemia has led to the rapid adoption of treatment strategies such as unrelated donor hematopoietic stem cell transplant and tyrosine kinase inhibitors into clinical practice, despite a relative paucity of randomized clinical trials. Recently, there has been a surge of interest in the underlying biology of ALL. In combination with an accumulation of more mature clinical study data in Philadelphia-positive ALL, it is increasingly possible to make more rational and informed treatment choices for patients of all ages. In this article, I review available data and indicate how I personally interpret current evidence to make pragmatic treatment choices with my patients, outside of clinical trials. My strongest recommendation is that all physicians who are treating this rare disease actively seek appropriate clinical trials for their patients wherever possible.
Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: Results from the International ALL Trial MRC UKALLXII/ECOG2993
2009, Blood
Prospective data on the value of allogeneic hematopoietic stem cell transplantation (alloHSCT) in Philadelphia chromosome–positive (Ph⁺) acute lymphoblastic leukemia (ALL) are limited. The UKALLXII/ECOG 2993 study evaluated the outcome of assigning alloHSCT with a sibling (sib) or matched unrelated donor (MUD) to patients younger than 55 years of age achieving complete remission (CR). The CR rate of 267 patients, median age 40, was 82%. Twenty-eight percent of patients proceeded to alloHSCT in first CR. Age older than 55 years or a pre-HSCT event were the most common reasons for failure to progress to alloHSCT. At 5 years, overall survival (OS) was 44% after sib alloHSCT, 36% after MUD alloHSCT, and 19% after chemotherapy. After adjustment for sex, age, and white blood count and excluding chemotherapy-treated patients who relapsed or died before the median time to alloHSCT, only relapse-free survival remained significantly superior in the alloHSCT group (odds ratio 0.31, 95% confidence interval 0.16-0.61). An intention-to-treat analysis, using the availability or not of a matched sibling donor, showed 5-year OS to be nonsignificantly better at 34% with a donor versus 25% with no donor. This prospective trial in adult Ph⁺ ALL indicates a modest but significant benefit to alloHSCT. This trial has been registered with clinicaltrials.gov under identifier NCT00002514 and as ISRCTN77346223.
Tanshinone IIA potentiates the efficacy of imatinib by regulating the AKT-MDM2-P53 signaling pathway in Philadelphia chromosome-positive acute lymphoblastic leukemia
2022, Oncology Letters
IRF4 deficiency vulnerates B progeny for leukemogenesis via Jak3 mutations resembling Ph-like B-ALL in humans
2021, Research Square

View all citing articles on Scopus

View full text

Philadelphia-chromosome-positive adult acute lymphocytic leukemia: Characteristics, treatment results, and prognosis in 41 patients

Abstract

Am J Med

Blood

Blood

Blood

Blood

Am J Med

Blood

The Philadelphia chromosome in adults presenting with acute leukemia

Philadelphia positive acute lymphoblastic leukemia in adults: age distribution, bcr breakpoint and prognostic significance

Leukemia

Structural organization of the bcr gene and its role in the Ph' translocation

Nature

The chronic myelogenous leukemia-specific p210 protein is the product of the bcr/abl hybrid gene

Science

The molecular genetics of Philadelphia chromosome-positive leukemias

NEJM

A new fused transcript in Philadelphia chromosome positive acute lymphocytic leukemia

Nature

A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia

Nature